Project 1: Finding pathogenetic steps. Accelerated plasma cell tumor formation occurs in BALB/c-Bcl-xL transgenic mice given a single intraperitoneal injection of pristane. This generates a chronic inflammatory tissue (oil granuloma) in which the tumors exclusively develop. 90+ percent of the mice develop a plasma cell tumor by day 100 in contrast to 60% at day 300 when three doses of pristane is given to BALB/c mice. The oil granuloma is invaded by large numbers of B-lymphocytes that form aggregates. Some of the lymphocytes that escape the aggregate become proliferating plasma cells. This is a new step or stage in plasmacytomagenesis. Fluorescence In Situ Hybridization of the plasma cells associated with these aggregates shows that IgH/C-Myc chromosomal translocations can be found by day 14 post pristane. Analysis of the B cells in the aggregates for Activation Induced Cytidine Deaminase is in progress. The basic question is whether the oncogenic chromosomal translocation takes place at this new late stage of development. Project 2: Inhibition of Plasma Cell Tumor Development The high predictable incidence of plasma cell tumors in pristane induced models makes it possible to test potential inhibitors. The nonsteroidal anti inflammatory agents indomethacin or sulindac administered continuously for 200-300 days in the diet are powerful inhibitors of pristane induced plasma cell tumor formation. In collaborative experiments with Jim Mitchell we have found the free radical scavenger Tempol substantially but not completely inhibits non-accelerated plasma cell tumor formation. PolyIC an interferon gamma stimulator in a first experiment with Sam Baron partially inhibits plasma cell tumor development. To test these effects in the accelerated model current experiments are designed to find the minimal amount of pristane required to initiate tumor formation and to maximize the inhibitory effects of Tempol and polyIC . Other shorter-acting agents such as squalene or alum that might be alternatives to pristane are being tested. The inhibition of IgH/C-Myc chromosomal translocations is also being tested by inducing plasma cell tumors in mice that are genetically defective for Activation Induced Cytidine Deaminase and Deoxy uracil glycosylase has shown former mice were partially but not completely resistant to developing IgH/C-Myc chromosomal translocations while the latter are strongly resistant. Thus, preventing chromosomal translocations can inhibit plasma cell tumorigenesis.